Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S930/00—Peptide or protein sequence
  • Y10S930/01—Peptide or protein sequence
  • Y10S930/19—Antibiotic
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S930/00—Peptide or protein sequence
  • Y10S930/01—Peptide or protein sequence
  • Y10S930/27—Cyclic peptide or cyclic protein

Definitions

• This invention relates to synergistine derivatives and their use.
• Pristinamycin and virginiamycin are known synergistine derivatives having antibacterial activity, see J. Preud'homme et al., Bull. Soc. Chim. Fr., 2, 585-91 (1968).
• the present invention provides new synergistine derivatives of the formula: ##STR2## in which Y represents a hydrogen atom or a dimethylamino radical and
• R 1 and R 2 each represent a hydrogen atom and R represents a pyrrolidin-3-ylthio or piperidin-3-ylthio or piperidin-4-ylthioradical (these radicals being optionally substituted by an alkyl radical), or alternatively R represents an alkylthio radical substituted by one or two hydroxysulphonyl radicals or alkylamino or dialkylamino radicals (optionally substituted by a mercapto or dialkylamino radical) or by one or two rings chosen from piperazino (optionally substituted by an alkyl or mercaptoalkyl radical), morpholino, thiomorpholino, piperidino, pyrrolidin-1-yl, piperidin-2-yl, piperidin-3-yl or piperidin-4-yl and pyrrolidin-2-yl or pyrrolidin-3-yl (these last five rings being optionally substituted on the nitrogen atom by an alkyl radical), or
• R 1 and R 2 together form a valence bond and R represents a pyrrolidin-3-ylamino, piperidin-3-ylamino or piperidin-4-ylamino, pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy, pyrrolidin-3-ylthio, piperidin-3-ylthio or piperidin-4-ylthio radical (these radicals being optionally substituted on the nitrogen atom of the ring by an alkyl radical), or alternatively R represents an alkylamino, alkoxy or alkylthio radical substituted by one or two hydroxysulphonyl radicals, alkylamino or dialkylamino radicals (optionally substituted by a dialkylamino radical) or trialkylammonio or imidazol-4-yl, or imidazol-5-yl radicals or by one or two rings chosen from piperazino (optionally substituted by an alkyl
• the compounds of the formula (I) in which Y is defined as above and the other symbols are defined as above under (a) can be prepared by reacting a compound of the formula:
• the reaction is generally carried out in an organic solvent e.g. an alcohol such as methanol or a chlorinated solvent such as chloroform, or a mixture of these solvents, at a temperature of between 0° C. and the reflux temperature of the reaction mixture, preferably at a temperature of the order of 20° C.
• an organic solvent e.g. an alcohol such as methanol or a chlorinated solvent such as chloroform, or a mixture of these solvents
• Compounds of the formula (III) can be prepared by reacting an alkali metal borohydride, in the presence of a strong organic acid, with a compound of the formula: ##STR4## in which Y is defined as above and R 1 and R 2 are alkyl radicals containing 1 to 4 carbon atoms or together form, with the nitrogen atom to which they are bonded, a 5-membered or 6-membered heterocycle optionally containing another heteroatom chosen from oxygen, nitrogen or sulphur.
• the reaction is generally carried out with sodium borohydride or cyanoborohydride in an organic solvent e.g. an ether such as tetrahydrofuran or an alcohol such as isopropanol, in the presence of a strong organic acid such as trifluoroacetic acid, at a temperature of between 0° C. and the reflux temperature of the reaction mixture, preferably at a temperature of the order of 20° C.
• an organic solvent e.g. an ether such as tetrahydrofuran or an alcohol such as isopropanol
• the compounds of the formula (V) can be prepared by the methods described by H. BREDERECK et al., Chem. Ber., 101, 41 and 3058 (1968) and Chem. Ber., 106, 3725 (1973).
• the compounds of the formula (I) in which Y is defined as above and the other symbols are defined as above under (b), except that R cannot represent a pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy or alkoxy radical (optionally substituted as defined under (b)), are prepared by reacting a compound of the formula:
• R" has the definition of R given above under (b), except that it cannot represent a pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy or alkoxy radical (optionally substituted as defined under (b)), with a compound of the formula (IV) in which Y is defined as above and R 1 and R 2 , which are identical or different, represent a hydrogen atom, a phenyl or pyridyl radical which is optionally substituted (by a dialkylamino radical of which the alkyl part contains 1 to 4 carbon atoms in a linear or branched chain), an alkyl radical containing 1 to 10 carbon atoms in a linear branched chain, which is optionally substituted (by a hydroxyl, mercapto, carboxyl, pyridyl or anilino radical or an alkylamino or dialkylamino radical of which at least one of the alkyl parts is itself substituted by a hydroxyl,
• the reaction is carried out in an organic medium, in the presence of an acid (e.g. acetic acid or a mixture of acetic acid and catalytic quantities of trifluoroacetic acid), in the presence or absence of a solvent, at a temperature of between 0° and 50° C., preferably at a temperature of the order of 20° C.
• an acid e.g. acetic acid or a mixture of acetic acid and catalytic quantities of trifluoroacetic acid
• the solvents can be chosen from organic solvents such as ethers (tetrahydrofuran), alcohols (ethanol) or chlorinated solvents (e.g. methylene chloride or chloroform).
• organic solvents such as ethers (tetrahydrofuran), alcohols (ethanol) or chlorinated solvents (e.g. methylene chloride or chloroform).
• the compounds of the formula (I) in which Y is defined as above and the other symbols are as defined above under (b) are prepared by reacting a compound of the formula:
• R"' is defined in the same way as R under (b), with a compound of the formula: ##STR7## in which Y is defined as above and Z represents a halogen atom, a trimethylsilyloxy or dialkoxyphosphoryloxy radical or a radical of the formula:
• R 3 is an alkyl, trifluoromethyl or trichloromethyl radical or a phenyl radical optionally substituted by a halogen atom or by an alkyl or nitro radical
• R 4 is defined in the same way as R 3 or represents an alkylcarbonylmethyl, alkylcarbonylethyl, alkoxycarbonylmethyl, 2-alkoxycarbonylethyl or alkoxy radical. If Z represents a halogen atom, it is chosen from chlorine and bromine.
• the reaction is generally carried out in an organic solvent e.g. an ether such as tetrahydrofuran, an alcohol such as ethanol or a chlorinated solvent (e.g. methylene chloride or chloroform), at a temperature of the order of 20° C.
• organic solvent e.g. an ether such as tetrahydrofuran, an alcohol such as ethanol or a chlorinated solvent (e.g. methylene chloride or chloroform)
• the reaction may be carried out in a basic medium, e.g. in the presence of an alkali metal hydride or an alkali metal alcoholate (e.g. sodium ethylate or potassium tert.-butylate).
• reaction can also be carried out either in a neutral medium, at a temperature of between 0° and 50° C., in one of the above-mentioned solvents, or in an acid medium under identical conditions to those described above for process B/.
• the compounds of the formula (IX) can be prepared by acid hydrolysis of compounds of the formula (IV) to give a compound of the formula: ##STR8## this being followed by: either ( ⁇ ) reaction with a compound of the formula:
• X represents a halogen atom and Z' has the definition given above for Z, except that it cannot represent a halogen atom, or ( ⁇ ) reaction with a halogenating agent, e.g. a compound of the formula:
• the hydrolysis of the compound of the formula (IV) to give the compound of the formula (X) is carried out with an aqueous solution of a mineral acid.
• the reaction is carried out using e.g. a 0.1N aqueous solution of hydrochloric acid at a temperature of the order of 20° C.
• the reaction of the compound of the formula (XI) with the compound of the formula (X) is generally carried out in an organic solvent such as methylene chloride, in the presence of an acid acceptor such as an organic base, e.g. triethylamine, or an inorganic base, e.g. an alkali metal carbonate or bicarbonate such as sodium bicarbonate or potassium bicarbonate.
• an organic solvent such as methylene chloride
• an acid acceptor such as an organic base, e.g. triethylamine, or an inorganic base, e.g. an alkali metal carbonate or bicarbonate such as sodium bicarbonate or potassium bicarbonate.
• the reaction temperature is generally between -20° and +20° C.
• reaction of the compound of the formula (XII) with the compound of the formula (X) is generally carried out in a chlorinated solvent such as methylene chloride, at a temperature of between -20° and +20° C.
• the radicals R', R" and R"' in the products of the general formulae (II), (VII) and (VIII) contain a secondary amine group, it may be necessary to protect it before reacting the corresponding products with the products of the general formulae (III), (IV) and (X) respectively.
• the protecting radical is removed after the reaction. This is carried out using any customary blocking means employed for protecting a secondary amine group, which does not affect the rest of the molecule and which is easily removed. It is particularly advantageous to use the trifluoroacetyl radical as the protecting radical; this can then be removed using an aqueous solution of an alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate.
• the new synergistines of the formula (I) can be purified by the usual known methods such as crystallization, chromatography or successive extractions in an acidic or basic medium.
• basic medium is understood as meaning a medium which is just sufficiently alkaline to free the parent substance from its acid addition salt, i.e. a medium whose pH does not exceed 7.5 to 8.
• the compounds of the formula (I) in which R represents a radical containing an amine group can be converted in to addition salts with acids by reaction with an acid in an organic solvent such as an alcohol, a ketone, an ester or a chlorinated solvent.
• the salt precipitates, if appropriate after concentration of its solution; it is separated off by filtration or decantation.
• the acid addition salts can also be obtained in the form of aqueous solutions by the addition of an aqueous solution of the corresponding acid to the compound of the formula (I).
• R represents a radical substituted by one or two hydroxysulphonyl radicals
• R represents a radical substituted by one or two hydroxysulphonyl radicals
• Known synergistines obtained by fermentation are used by doctors for the treatment of many complaints caused by Gram-positive bacteria (of the genus Staphylococcus, Streptococcus, Pneumococcus or Enterococcus) and Gramnegative bacteria (of the genus Haemophilus, Gonococcus or Meningococcus).
• known compounds have the disadvantage of being insoluble in an aqueous medium and they can therefore only be administered orally, generally in the form of capsules, coated tablets or ordinary tablets.
• the compounds according to the invention have the considerable advantage of being able to be solubilized in water, in the form of salts, at therapeutically usable doses while at the same time retaining the general spectrum of activity of synergistines. They are especially active in vitro against Staphylococcus aureus Smith at concentrations of between 0.1 and 125 ⁇ g/ml.
• Their toxicity is generally low. Their LD 50 is generally greater than 300 mg/kg, administered subcutaneously to mice.
• the compounds of the invention can be employed as such, i.e. in the form of the base, but for use in aqueous solution, which constitutes the main advantage of the products of the invention, it is particularly advantageous to employ their pharmaceutically acceptable salts, i.e. salts which are non-toxic at the use doses.
• salts which may be mentioned are the addition salts with mineral acids, such as hydrochlorides, hydrobromides, sulphates, nitrates and phosphates, or with organic acids, such as acetates, propionates, succinates, maleates, fumarates, methanesulphonates, p-toluenesulphonates and isethionates, or substitution derivatives of these compounds.
• mineral acids such as hydrochlorides, hydrobromides, sulphates, nitrates and phosphates
• organic acids such as acetates, propionates, succinates, maleates, fumarates, methanesulphonates, p-toluenesulphonates and isethionates, or substitution derivatives of these compounds.
• Other pharmaceutically acceptable salts which may be mentioned are the quaternary ammonium salts if R represents a trialkylammonio radical; these salts correspond to the anions of the salts listed
• salts with alkali metals such as the sodium, potassium and lithium salts
• the salts with alkaline earth metals such as the calcium or magnesium salt
• the ammonium salt and the addition salts with organic nitrogen bases such as ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N,N-dimethylethanolamine, benzylamine, dibenzylamine, dicyclohexylbenzylamine, N-benzyl- ⁇ -phenethylamine, N,N'-dibenzylethylenediamine, benzhydrylamine, arginine, leucine, lysine or N-methylglucamine.
• alkali metals such as the sodium, potassium and lithium salts
• the salts with alkaline earth metals such as the calcium or magnesium salt
• the ammonium salt and the addition salts with organic nitrogen bases such as ethanolamine, diethanolamine, trimethylamine, triethyl
• R 1 and R 2 each represent a hydrogen atom and R represents a piperidin-4-ylthio radical unsubstituted or substituted by an alkyl radical, or an alkylthio radical substituted by one or two dialkylamino radicals, each optionally substituted by a mercapto radical, or alkylpiperazino or mercaptoalkylpiperazino radicals,
• R 1 and R 2 together form a valence bond and R represents a piperidin-3-ylamino, piperidin-4-ylamino, piperidin-3-ylthio, or piperidin-4-ylthio unsubstituted or substituted on the nitrogen atom of the ring by an alkyl radical, or alternatively R represents an alkylamino, alkoxy or alkylthio radical substituted by one or two hydroxysulphonyl radicals, alkylamino or dialkylamino radicals, optionally substituted by another dialkylamino radical, or trialkylamino, imidazol-4-yl, imidazol-5-yl alkylpiperazino, morpholino, piperidino, pyrrolidinyl or N-alkylpyrrolidinyl radicals.
• R 1 and R 2 each represent a hydrogen atom and R represents an alkylpiperidin-4-ylthio radical or an alkylthio radical substituted by one or two dialkylamino or alkylpiperazino radicals,
• R 1 and R 2 together form a valence bond and R represents a 1-alkylpiperidin-4-ylamino radical, or alternatively R represents a straight-chain alkylamino radical substituted by an alkylamino or dialkylamino radical of which the alkyl parts may form, with the nitrogen atom to which they are attached, a heterocycle chosen from pyrrolidin-1-yl, piperidino and 4-alkylpiperazino, or by a 1-alkylpyrrolidin-2-yl radical, or alternatively R represents a straight-chain alkylthio radical substituted by a 4-alkylpiperazino radical or represents a 5-dialkylaminopent-2-yl radical,
• R 1 and R 2 together form a valence bond and R represents a 1-alkylpiperidin-4-ylamino radical, it being understood that the said alkyl portions and radicals are linear or branched and contain 1 to 3 carbon atoms each.
• NMR spectra of the products described in these examples have general characteristics which are common to all the products and particular characteristics which are peculiar to each of the products according to the nature of the substituents Y, R 1 and R 2 .
• Example 1 the assignment of all the protons in the molecule is given; in the following examples, only the particular characteristics due to the variable radicals are mentioned. All the protons are designated according to the numbering indicated in the general formula (XIII) and recommended by J. O. ANTEUNIS et al. [Eur. J. Biochim., 58, 259 (1975)]. ##
• Examples 2 to 50 the following are given respectively in brackets: the chemical shift, the shape of the signal, the integration (number of protons, if appropriate with the percentage of isomer) and the assignment of the protons.
• flash chromatography is understood as meaning a purification technique which comprises using a short chromatography column and operating under a moderate pressure (50 kPa) using a silica of particle size 40-63 ⁇ m, as described by W. C. STILL, M. KAHN and A. MITRA [J. Org. Chem., 43, 2923 (1978)].
• 3-Dimethylaminopropanethiol (1.95 g) is added to a solution of 5 ⁇ -methylenepristinamycin I A (3.6 g) in a mixture of methanol (25 cc) and chloroform (5 cc) and the solution obtained is then stirred for 20 hours at a temperature of the order of 20° C.
• the reaction mixture is then poured into distilled water (250 cc); the emulsion obtained is extracted 3 times with methylene chloride (250 cc in total).
• the organic phases are combined, dried over magnesium sulphate and filtered and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) at 30° C.
• the 5 ⁇ -methylenepristinamycin I A can be prepared in the following manner:
• the 5 ⁇ -dimethylaminomethylenepristinamycin I A can be prepared in the following manner:
• the 5 ⁇ -methylenevirginiamycin S can be prepared in a manner analogous to that described in Example 1 for 5 ⁇ -methylenepristinamycin I A , but starting from 5 ⁇ -dimethylaminomethylenevirginiamycin S (2 g) and sodium cyanoborohydride (74 mg). After purification by "flash” chromatography [eluent: chloroform/methanol (98/2 by volume)] and concentration to dryness of fractions 2 to 5 under reduced pressure (2.7 kPa) at 30° C., 5 ⁇ -methylenevirginiamycin S (1 g) is obtained in the form of a beige powder melting at about 190° C.
• the 5 ⁇ -dimethylaminomethylenevirginiamycin S can be obtained by following a procedure analogous to that described in Example 1 for 5 ⁇ -diimethylaminomethylenepristinamycin I A , but starting from virginiamycin S (2 g) and bis(dimethylamino)tert.-butoxymethane (10 cc), and after purification by "flash" chromatography [eluent: chloroform/methanol (98/2 by volume)] and concentration to dryness of fractions 9 to 12 under reduced pressure (2.7 kPa) at 30° C., 5 ⁇ -dimethylaminomethylenevirginiamycin S (0.8 g) is obtained in the form of a yellow powder melting at about 175° C.
• the 2-(4-methylpiperazin-1-yl)ethanethiol can be prepared according to the method described by D. D. REYNOLDS et al., J. Org. Chem. 26, 5125 (1961).
• the 3-(4-methylpiperazin-1-yl)propanethiol can be prepared as below in Example 41.
• the 1,3-bis(dimethylamino)propane-2-thiol can be prepared as below in Example 39.
• the 1-methyl-4-mercaptopiperidine can be prepared according to the method described by H. BARRER and R. E. LYLE, J. Org. Chem. 27, 641 (1962).
• the 1-diethylaminopropane-2-thiol can be prepared according to the method described by R. T. WRAGG, J. Chem. Soc. (C), 2087 (1969).
• the 1,4-bis(2-mercaptoethyl)piperazine can be prepared according to the method described by D. D. REYNOLDS, M. K. MASSAD, D. L. FIELDS and D. L. JOHNSON, J. Org. Chem. 26, 5111 (1961).
• 2-Dimethylaminoethylamine (5.3 g) is added dropwise to a solution of 5 ⁇ -dimethylaminomethylenepristinamycin I A (5.5 g) in acetic acid (60 cc) so as not to exceed 25° C.
• the solution obtained is stirred for 20 hours at a temperature of the order of 20° C. and is then poured slowly into a saturated aqueous solution of sodium bicarbonate; the mixture obtained is extracted twice with methylene chloride (750 cc in total).
• the organic phases are combined, dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 30° C.
• the 3-amino-1-methylpiperidine can be prepared according to the method described by L. M. WERBEL, A. CURRY, E. F. ELSLAGER and C. HESS, J. Heterocyclic Chem. 10, 363 (1973).
• the 4-amino-1-methylpiperidine can be prepared by the method described by E. F. ELSLAGER, L. M. WERBEL, A. CURRY, N. HEADEN and J. JOHNSON, J. Med. Chem. 17, 99 (1974).
• the 1-(2-aminoethyl)-4-methylpiperazine can be prepared in the following manner:
• N-Methylpiperazine (9.75 g) is added to a solution of 2-bromoethylamine hydrobromide (10.0 g) in absolute ethanol (60 cc). The solution obtained is stirred for 16 hours at a temperature of the order of 20° C. and the ethanol is then removed under reduced pressure (2.7 kPa) at 30° C. The oily residue is taken up with chloroform (50 cc); the mixture obtained is stirred with a 10N aqueous solution of sodium hydroxide (20 cc). The aqueous phase is extracted 3 times with chloroform (150 cc in total).
• 2-Dimethylaminoethanethiol (2.1 g) is added to a solution of 5 ⁇ -dimethylaminomethylenepristinamycin I A (1.84 g) in acetic acid (40 cc). The solution obtained is stirred for 20 hours at a temperature of the order of 20° C. and is then poured slowly into a saturated aqueous solution of sodium bicarbonate; the mixture obtained is extracted 3 times with methylene chloride (400 cc in total). The organic phases are combined, dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 30° C.
• the 3-dimethylamino-2-methylpropanethiol can be prepared in the following manner:
• N,N-dimethyl-3-acetylthio-2-methylpropylamine can be prepared in the following manner:
• N,N-dimethyl-1-chloro-2-methylpropylamine can be prepared according to the method described by J. P. BOURQUIN et al., Helv. Chim. Acta, 41, 1072 (1958).
• the 2-dimethylamino-2-methylpropanethiol can be prepared according to the method described by H. R. SNYDER, J. M. STEWART and J. B. ZIEGLER, J. Am. Chem. Soc., 69, 2672 (1947).
• the 2-(pyrrolidin-1-yl)ethanethiol can be prepared according to the method described by J. W. HAEFFELE and R. W. BROGE, Proc. Sci. Toilet Goods Assoc. 32, 52 (1959) [Chem. Abstr. 54, 17234e (1960)].
• the 2-(1-methylpyrrolidin-2-yl)ethanethiol can be prepared by a procedure analogous to that described in Example 32 for preparing 3-dimethylamino-2-methylpropanethiol, but starting from 2-(2-acetylthioethyl)-1-methylpyrrolidine (15.7 g) and sodium (0.07 g). This gives a product (12.2 g) in the form of a red oil.
• the 2-(2-acetylthioethyl)-1-methylpyrrolidine can be prepared by a procedure analogous to that described in Example 32 for preparing N,N-dimethyl-3-acetylthio-2-methylpropylamine, but starting from 2-(2-chloroethyl)-1-methylpyrrolidine (12.7 g) and thiolacetic acid (6.8 cc). This gives a product (15.7 g) in the form of a red oil.
• the 4-mercapto-1-methylpiperidine can be prepared according to the method described by H. BARRER and R. E. LYLE, J. Org. Chem. 27, 641 (1962).
• the 1-ethyl-3-mercaptopiperidine can be prepared according to the method described by J. H. BIEL et al., J. Am. Chem. Soc. 77, 2250 (1955).
• the N-(2-mercaptoethyl)-N,N',N'-trimethylethylenediamine can be prepared in the following manner: ethyl 2-mercaptoethyl carbonate (5.0 g) is added to a solution of N,N',N'-trimethylethylenediamine (10.2 g) in toluene (40 cc), heated under reflux. After 5 hours under reflux, the toluene is removed under reduced pressure (2.7 kPa) at 50° C. and the residue is distilled at this pressure. This gives N-(2-mercaptoethyl)-N,N',N'-trimethylethylenediamine in the form of a yellow liquid distilling at 105° C. under 2.7 kPa.
• the ethyl 2-mercaptoethyl carbonate can be prepared according to the method described by D. D. REYNOLDS, D. L. FIELDS and D. L. JOHNSON, J. Org. Chem. 26, 5125 (1961).
• the 1,3-bis(dimethylamino)propane-2-thiol can be prepared according to the method described by J. M. STEWART, J. Org. Chem., 29, 1655 (1964).
• the 1-(2-mercaptoethyl)-4-methylpiperazine can be prepared according to the method described by D. D. REYNOLDS et al., J. Org. Chem. 26, 5125 (1961).
• the 1-(3-mercaptopropyl)-4-methylpiperazine can be prepared in a manner analogous to that described in Example 32 for preparing 3-dimethylamino-2-methylpropanethiol, but starting from 1-(3-acetylthiopropyl)-4-methylpiperazine (109 g) and sodium (0.46 g). This gives 1-(3-mercaptopropyl)-4-methylpiperazine (64.8 g) in the form of a yellow oil distilling at 133° C. under 0.13 kPa.
• the 1-(3-acetylthiopropyl)-4-methylpiperazine can be prepared in a manner analogous to that described in Example 32 for preparing N,N-dimethyl-3-acetylthio-2-methylpropylamine, but starting from 1-(3-chloropropyl)-4-methylpiperazine (138 g) and thiolacetic acid (68.5 g). This gives 1-(3-acetylthiopropyl)-4-methylpiperazine (109 g) in the form of a yellow oil distilling at about 160° C. under 0.13 kPa.
• the 3-mercapto-2-methylpropylammonium iodide can be prepared in the following manner: sodium methylate (0.024 g) is added to a solution of 3-acetylthio-2-methylpropylammonium iodide (3.6 g) in methanol (18 cc) at a temperature of the order of 20° C. The mixture obtained is heated under reflux for 1 hour and then left at ambient temperature for 16 hours. The methanol is removed under reduced pressure (2.7 kPa) at 50° C. The residue is stirred for 1 hour with isopropanol (35 cc), the white suspension is filtered and the material on the filter is then dried. This gives 3-mercapto-2-methylpropylammonium iodide (3.1 g) in the form of a beige powder melting at 120° C.
• the 3-acetylthio-2-methylpropylammonium iodide can be prepared in the following manner: methyl iodide (1.4 cc) is added to a solution of N,N-dimethyl-3-acetylthio-2-methylpropylamine (3.5 g) in acetonitrile (35 cc); after stirring for 18 hours at a temperature of the order of 20° C., the precipitate is filtered off and then dried. This gives 3-acetylthio-2-methylpropylammonium iodide (3.8 g) in the form of a white powder melting at 181° C.
• the infra-red spectrum contains the bands characteristic of pristinamycins: 1745, 1680, 1650, 1525, 815, 740 and 705 cm -1 , plus the bands characteristic of the group --SO 3 H [1200 cm -1 (broad) and 1050 cm -1 ].
• the reaction mixture is stirred for 16 hours at a temperature of the order of 20° C. and then diluted with methylene chloride (500 cc) and distilled water (100 cc). After stirring, the aqueous phase is extracted twice with methylene chloride (50 cc in total).
• the 1-(2-mercaptopropyl)-4-methylpiperazine is prepared by heating a mixture of propylene sulphide (19 cc) and N-methylpiperazine (29 cc) at 100° C. for 16 hours. This gives a colourless oil (32 g) distilling at 105° C. under 1.3 kPa.
• the 5 ⁇ -(4-methylphenyl)sulphonyloxymethylenepristinamycin I A can be obtained in the following manner:
• Triethylamine (0.42 cc) and then p-toluenesulphonyl chloride (0.57 g) are added, at a temperature of the order of -30° C., to a solution of 5 ⁇ -hydroxymethylenepristinamycin I A (2.7 g) in methylene chloride (30 cc).
• the reaction mixture is subsequently stirred for 2 hours at a temperature of the order of 20° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at 30° C.; the residue obtained is purified by "flash" chromatography [eluent: methylene chloride/methanol (96/4 by volume)].
• the 5 ⁇ -hydroxymethylenepristinamycin I A can be prepared in the following manner:
• 5 ⁇ -Dimethylaminomethylenepristinamycin I A (10.6 g) is added, with stirring, to a 0.1N aqueous solution of hydrochloric acid (420 cc). The solution obtained is then stirred for 3 hours at a temperature of the order of 20° C. A saturated aqueous solution of sodium bicarbonate (30 cc) is then added dropwise so as to give a pH of the order of 4. The product which precipitates is filtered off and then washed 3 times with distilled water (30 cc in total). After drying under reduced pressure (2.7 kPa) at a temperature of the order of 20° C., 5 ⁇ -hydroxymethylenepristinamycin I A (9.5 g) is obtained in the form of a beige powder. This product is of sufficient quality to be used as such in the subsequent stages. However, it can be purified in the following manner:
• the 1-dimethylaminopropane-2-thiol can be prepared according to the method described by S. D. TURK et al., J. Org. Chem. 29, 974 (1964).
• the 5-diethylaminopentane-2-thiol can be prepared in a manner analogous to that described in Example 32 for preparing 3-dimethylamino-2-methylpropanethiol, but starting from N,N-diethyl-4-acetylthiopentan-1-amine (4.0 g) and sodium (0.046 g). After purification by "flash” chromatography [eluent: ethyl acetate/methanol (70/30 by volume)] and concentration to dryness of fractions 16 to 24, 5-diethylaminopentane-2-thiol (2.0 g) is obtained in the form of a yellow oil.
• N,N-diethyl-4-acetylthiopentan-1-amine can be prepared in a manner analogous to that described in Example 32 for preparing N,N-dimethyl-3-acetylthio-2-methylpropylamine, but starting from N,N-diethyl-4-chloropentan-1-amine (32 g) and thiolacetic acid (15.2 g). This gives a product (4.31 g) in the form of a yellow oil.
• the N,N-diethyl-4-chloropentan-1-amine can be prepared according to the method described by M. S. KHARASH and C. F. FUCHS, U.S. Pat. No. 2,432,905.
• 4-Amino-1-methylpiperidine (0.12 g) is added, at a temperature of the order of 20° C., to a solution of 5 ⁇ -(4-methylphenyl)sulphonyloxymethylenepristinamycin I A (0.5 g) in ethanol (25 cc). After stirring for 16 hours at this temperature, the reaction mixture is diluted with methylene chloride (100 cc) and washed twice with distilled water (100 cc in total). The organic phase is dried over sodium sulphate and then concentrated under reduced pressure (2.7 kPa) at 30° C. The residue is stirred with ethyl ether (15 cc). After filtration, 5 ⁇ -(1-methylpiperidin-4-yl)aminomethylenepristinamycin I A (0.42 g) is obtained in the form of a white powder, the characteristics of which are identical to those described in Example 24.
• a 4N ethanolic solution of gaseous ammonia (10 cc) is added slowly to a solution of 5 ⁇ -dimethylaminomethylenepristinamycin I A (1.84 g) in acetic acid (20 cc).
• the solution obtained is stirred for 20 hours at a temperature of the order of 20° C. and then poured slowly into a saturated aqueous solution of sodium bicarbonate (200 cc).
• the suspension obtained is extracted 3 times with methylene chloride (300 cc in total); the organic phases are combined, dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 30° C.
• Acetyl chloride (0.14 cc) is added, at a temperature of the order of -20° C., to a solution of 5 ⁇ -hydroxymethylenepristinamycin I A (1.8 g) in methylene chloride (20 cc) containing triethylamine (0.2 g), and the temperature is then allowed to rise to about 20° C.
• reaction mixture is subsequently stirred for 20 hours at this temperature and then concentrated to dryness under reduced pressure (2.7 kPa) at 30° C.; the residue obtained is purified by "flash” chromatography [eluent: ethyl acetate]. After concentration to dryness of fractions 4 to 7 under reduced pressure (2.7 kPa) at 30° C., 5 ⁇ -acetoxymethylenepristinamycin I A (0.7 g) is obtained in the form of a yellow powder melting at about 160° C.
• the 5 ⁇ -hydroxymethylenepristinamycin I A can be prepared as described in Example 44.
• Example 30 By following a procedure analogous to the method described in Example 48, but stirring for 20 hours, the 5 ⁇ -(3-dimethylaminopropyl)thiomethylenepristinamycin I A described above in Example 30 is prepared from 5 ⁇ -chloromethylenepristinamycin I A .
• the starting material can be prepared in the following manner:
• a stream of chlorine gas is passed through a solution of triphenyl phosphite (1.3 cc) in methylene chloride (25 cc) until a persistent greenish yellow colour is obtained, the temperature being kept at between -20° C. and -15° C.
• Triphenyl phosphite (6 drops) is then added in order to decolourize the solution, this being followed by 5 ⁇ -hydroxymethylenepristinamycin I A (4.1 g), the temperature still being kept at between -20° C. and -15° C.
• the solution obtained is stirred for 1 hour at -15° C. and a solution of pyridine (0.4 cc) in methylene chloride (25 cc) is then added dropwise.
• the mixture is washed 4 times with distilled water (100 cc in total); the organic phase is dried over magnesium sulphate and filtered and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) at 30° C.
• compositions comprising a compound of the formula (I), in the free form or in the form of an addition salt with a pharmaceutically acceptable acid, or if appropriate, a pharmaceutically acceptable base, in association with a pharmaceutically acceptable diluent or adjuvant.
• compositions can be administered parenterally, orally rectally or topically.
• Sterile compositions for parenteral administration are preferably suspensions, emulsions or aqueous or non-aqueous solutions.
• Water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, e.g. ethyl oleate, or other suitable organic solvents can be employed as the solvent or vehicle.
• These compositions can also contain adjuvants, in particular wetting agents, agents for imparting isotonicity, emulsifiers, dispersants and stabilizers.
• Sterilization can be carried out in several ways, e.g. by filtration under aseptic conditions, by incorporating sterilizing agents into the composition, by irradiation or by heating.
• the compositions can also be prepared in the form of sterile solid compositions which can be dissolved in an injectable sterile medium at the time of use.
• compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active principle, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• Tablets, pills, powders or granules can be used as solid compositions for oral administration.
• the active product according to the invention (if appropriate in association with another pharmaceutically compatible product) is mixed with one or more inert diluents or adjuvants such as sucrose, lactose or starch.
• these compositions can also comprise substances other than diluents, e.g. a lubricant such as magnesium stearate.
• Solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil, and pharmaceutically acceptable emulsions can be used as liquid compositions for oral administration.
• These compositions can also comprise substances other than diluents, e.g. wetting, sweetening or flavouring products.
• compositions for topical administration can be e.g. creams, ointments, lotions, eye lotions, mouthwashes, nose drops or aerosols.
• the compounds of the invention are particularly useful in the treatment of infections of bacterial origin.
• the doses depend on the desired effect and the duration of the treatment. For an adult, they are generally between 2000 and 4000 mg per day, administered parenterally, in particular intravenously by slow perfusion.
• the physician will determine the dosage which he considers to be most appropriate as a function of the age, the weight and all the other factors peculiar to the subject to be treated.
• An injectable solution for perfusion containing 5 g/liter of active product and having the following composition, is prepared by the usual technique:
• An injectable solution for perfusion containing 5 g/liter of active product and having the following composition, is prepared by the usual technique:

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• 1983
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• 1984
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